Celebrating a decade of Canadian immunology published in Immunology & Cell Biology

On behalf of the Canadian Society for Immunology (CSI), it is our great pleasure to highlight a few of the many outstanding articles in Immunology & Cell Biology (ICB) authored by Canadian immunologists. This Virtual Issue is timed to coincide with the 34th annual spring meeting of the CSI, opening on 17 June 2022 in Halifax, Nova Scotia, Canada. This conference represents the long-awaited return to in-person scientific interactions, reuniting friends and colleagues from across the country and beyond. Like the Australian and New Zealand Society for Immunology (ASI), the CSI provides a central hub for immunology researchers spread across a very large geographic area. Our annual meetings build collaborations and a sense of community across vast distances, bringing together immunologists of all stripes from Canada's network of research centers stretching 7000 km from Victoria, British Columbia, to St John's, Newfoundland. Often held in retreat-like settings in the Rocky Mountains or the Southern Townships of Quebec, CSI meetings provide a collegial and supportive atmosphere where scientific interactions happen not just via formal talks, but through discussions over meals, lively poster sessions, and pints afterwards. Our meetings also traditionally provide an opportunity to network with outstanding scientists from our neighbors to the south, as exemplified by our Keynote speaker this year, Dr Anjana Rao. The collaborative networks of Canadian immunology extend around the globe, and opportunities abound to build and strengthen additional international interactions.

Despite our geographic distance, Canadian and Australian immunology is strongly connected and can flourish further through common scientific cultures, collaborations, trainee exchanges, and more. ICB is one vehicle supporting scientific interactions, with significant representation of Canadian scientists on the editorial board and among reviewers. The rigorous and fair review process developed at ICB is highly appreciated and has supported the publication of numerous high-quality Canadian studies, including those highlighted here and many more. Increasing the cross-fertilization between the CSI and ASI communities is an important goal for both societies. With this Virtual Issue as a launching point, we look forward to building new bridges connecting our trainees, scientists and meetings. Stay tuned! Follow the CSI and ASI on Twitter (@CdnImmunol and @ASImmunology).

The publications in this ICB Virtual Issue illustrate the highly collaborative and active training environments provided by Canadian immunologists. This collection highlights multiple research trainees as authors, in several cases as first authors. A key feature of Canadian science, and of the CSI, is the support of trainee development at all stages. This includes high school outreach activities, support for graduate students and postdoctoral fellows attending national and international conferences, opportunities for networking, and leadership development. A popular, and highly competitive, CSI poster award competition is often the first opportunity that graduate students have to show off their accomplishments to immunologists across the country. Over recent years, these activities have been supplemented by educational sessions and approaches to foster increased awareness and training in equity, diversity and inclusion. The support of early career scientists through travel awards, research recognition awards, involvement in national events, and a recently launched Early Career Investigator Webinar Series, are additional examples of CSI activities. This commitment to ensuring the success of the next generation of immunologists is shared by many of our sister societies worldwide, including the ASI. There has been a healthy traffic of trainees and early investigators between Australia and Canada, which supports international collaborations and helps to prepare the next generation of scientists to operate effectively in a global collaborative environment.

This Virtual Issue provides the opportunity to feature 12 articles published by CSI members that appeared between 2012 and 2022 in ICB. These articles highlight the depth, breadth, diversity and impact of immunological investigations led by Canadians from coast to coast to coast. The featured articles link several fundamental aspects of inflammation and immunity, often with significant implications for clinical translation.

Many Canadian research teams work on T cell thymic education and two articles included in this Issue highlight this broad area of research strength. Plumb et al.¹ demonstrated a cell-intrinsic requirement for interleukin (IL)-7 receptor signaling in the development of early thymic progenitors. This work thus defines a critical role for IL-7 very early in T cell development and extends the functions of this potent cytokine beyond its classic roles in T cell survival, homeostasis and proliferation. The findings of Plumb et al.¹ need to be considered in understanding the benefits of IL-7-based therapies. Quantifying the surface expression of CD5, a surrogate marker of basal T cell receptor (TCR) signal strength, Dong et al.² evaluated polyclonal immature and mature T cell pools in type 1 diabetes-prone and -resistant mouse strains. While non-obese diabetic (NOD) mice had no thymic selection bias towards generating thymocytes with high-affinity TCRs for self-peptides, they were found to harbor a greater number of mature CD8⁺ T cells with a high CD5 expression level in their lymph nodes. These findings suggest that peripheral CD8⁺ T cells with high-affinity TCRs may have a survival advantage in the NOD strain, widely used in immunologic studies.

Canadian research strengths in T cell homeostasis, activation, effector functions, and memory are also well represented in this issue. While differentiation of naïve CD4⁺ T cells into functional T helper lineages has been studied intensively, it remains unclear whether there is functional heterogeneity in naïve T cell compartments. Sood et al.³ explored the cytokine production capacities of naive CD4⁺ T cells bearing TCRs of varying strength, also judged by CD5 expression. The authors found that naïve CD5^lowCD4⁺ T cells produce more interferon (IFN)-γ than do their CD5^high counterparts, suggesting inherent functional biases prior to foreign antigen encounter. These differential naïve T cell potentials may need to be taken into consideration in understanding responses to infections and in designing future immunotherapies. A wide array of costimulatory molecules can regulate T cell activation, differentiation and survival, including 4-1BB (CD137). Lin et al.⁴ demonstrated that CD137–CD137 ligand interactions partially mediate the preferential accumulation of CD8⁺ memory T cells observed after in vivo treatment with IL-2/anti-IL-2 monoclonal antibody (mAb) complexes. As IL-2/IL-2 mAb complexes may be used clinically to direct IL-2 to select cell types, the role of CD137 signaling in this context is significant and worthy of further investigation.

Uncontrolled T cell activation can have catastrophic consequences, ranging from autoimmunity to lymphoma, which is avoided through the activities of a number of co-inhibitory molecules, including programmed cell death-1 (PD-1). Mathieu et al.⁵ demonstrated that Notch signaling directly controls Pdcd1 transcription. This pathway also regulates the surface expression of PD-1 during antigen- and mitogen-driven CD8⁺ T cell responses. These findings are exciting not only because PD-1 plays a part in self-tolerance but also in light of the promise of PD-1-based immune checkpoint inhibitors in the clinic. Regulatory T cells also play key roles in tempering immune responses, but can be targeted by pathogens to evade local inflammatory responses. For example, the mouse nematode Heligmosomoides polygyrus releases a transforming growth factor-β (TGF-β) mimic (Hp-TGM), which signals through TGF-β receptors to induce the expression of the master transcription factor forkhead box P3 (FOXP3) in CD4⁺ T cells. Cook et al.⁶ recently demonstrated that Hp-TGM can induce stable FOXP3 expression in human CD4⁺ T cells. Importantly, Hp-TGM-induced Treg cells were more potent than TGF-β-induced Treg cells in suppression assays and maintained their phenotypic characteristics in an inflammatory cytokine milieu. Therefore, Hp-TGM may be considered as a potential therapeutic molecule for chronic inflammatory disorders, including inflammatory bowel disease.

Unconventional innate-like T cells, including γδ T and invariant T cells, are also a subject of intense investigations led by several Canadian groups. Zarin et al.⁷ demonstrated how TCR-, Notch- and/or cytokine receptor-coupled signals could work collaboratively to generate functional γδ T cell subsets. For example, the optimal differentiation program to convert γδ T cell precursors to IL-17-producing cells required Notch and weak TCR ligands in the presence of IL-1β, IL-21 and IL-23. These cytokines were not only critical for IL-17 expression by mature γδ T cells but also for the intrathymic development of γδ17 cells. The culture conditions described in this work may be used to expand and skew γδ T cells for further experimental analyses or adoptive transfer investigations.

Invariant natural killer T (iNKT) cells are another subset of innate-like T lymphocytes that recognize glycolipid antigens, typified by α-galactosylceramide (α-GalCer). Gebremeskel et al.⁸ developed an in vivo protocol in which α-GalCer-loaded dendritic cells were injected to expand iNKT cells in mice. Importantly, the iNKT cells thus generated did not have a skewed TCR Vβ repertoire, were phenotypically similar to naïve iNKT cells and retained their functional competence. The protocol published by these investigators may be used for adoptive iNKT cell transfer and reconstitution studies. Hayworth et al.⁹ reported that mouse and human iNKT cells express certain TCR Vβ chains that could be targeted directly by staphylococcal and streptococcal exotoxins commonly known as bacterial superantigens (SAgs). SAg-driven iNKT cell activation was dependent on high-affinity MHC class II interactions, but not on CD1d. Therefore, this work revealed a novel pathway of inflammatory cytokine production in response to Gram-positive bacterial infections. The authors proposed that iNKT cells constitute an attractive target in the management of SAg-mediated illnesses, including but not limited to staphylococcal food poisoning and toxic shock.

To investigate how the therapeutic application of Toll-like receptor 2 (TLR2) activators can mobilize innate effector cells to inflammatory sites, Haidl et al.¹⁰ examined the mechanisms of TLR2-induced natural killer (NK) cell migration into the peritoneal cavity. Administration of TLR2 agonists led to robust elevation of several chemokines, including CCR2 ligands, and NK cell, but not neutrophil, recruitment was entirely dependent on CCR2. These results highlight the significance of NK cell functions in response to pathogens that naturally activate TLR2, and identify these cells as a component of the response to TLR2 agonist-based therapies.

Two studies highlighted in this Virtual Issue investigated novel molecules and molecular mechanisms associated with alternatively activated (M2) macrophages. Ayaub et al.¹¹ explored the impact of IL-6 on the differentiation of M2 macrophages in the presence of IL-4/IL-13. They found that IL-6 can promote M2 “hyper-polarization” with acquisition of a pro-profibrotic phenotype, and cause the expansion of the endoplasmic reticulum (ER). ER expansion was associated with activation of components of the unfolded protein response including IRE-XBP1, and inhibitors of the latter pathway prevented the IL-6-mediated enhancement of M2 polarization. This study thus identifies a targetable pathway to control the activities of M2 macrophages in multiple disease settings. Sanyal et al.¹² reported the differential expression pattern of the CD20 homolog MS4A4A on the cell surface of human monocyte, dendritic cell (DC) and plasma cell populations in the peripheral blood and bone marrow. They found this molecule to be selectively expressed on M2 macrophages and also to be present on malignant cell counterparts, including myeloid leukemias and myelomas. This study represents the first characterization of the cell surface expression of MS4A4A and identify this largely uncharacterized protein as a novel target for immunotherapy.

As we begin a new chapter in collaborations between Canadian, Australian and New Zealand Societies for Immunology, the appreciation of the Canadian science published in this excellent journal is a perfect place to start. This diverse collection of articles from groups across the country highlights the breadth and depth of Canadian immunology and the collaborative nature of science in Canada. Each of these studies embodies the commitment displayed by graduate students and postdoctoral scholars working together with their dedicated mentors in very supportive environments. We look forward to gathering in Halifax on 17 June 2022 to provide the opportunity for our current trainees to wow us with new and exciting results and have some fun, while recognizing their hard work and amazing accomplishments.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

SM Mansour Haeryfar: Conceptualization; writing – original draft; writing – review and editing. Jean S Marshall: Conceptualization; writing – original draft; writing – review and editing. Kamala Patel: Conceptualization; writing – original draft; writing – review and editing. Aaron Marshall: Conceptualization; writing – original draft; writing – review and editing.